tbuckley/cabot-search huggingface dataset:
Abstract LB089: Effective <i>in vivo</i> treatment of endometrial tumor models with coexistent mutant PI3K and PTEN inactivation with a selective bi-steric mTORC1 kinase inhibitor
Authors: Hilla Solomon, Radha Mukherjee, Xiaoping Chen, HuiYong Zhao, Elisa de Stanchina, Britta Weigelt, Alison M. Schram, Carol Aghajanian, Mallika Singh, Jan Smith, Neal Rosen
Journal: Cancer Research (2022)

Abstract Dysregulation of PI3K signaling is a common event in human cancer, but feedback inhibition of receptor kinase signaling and/or induction of PTEN translation by activated PI3K/AKT/mTOR signaling reduces pathway output and tumor dependency. In some cancers, including the majority of endometrial carcinomas, these lesions coexist and cause synergistic hyperactivation of pathway output, particularly mTORC1 kinase signaling. Although this suggests that PI3K signaling is a driver of these endometrial cancers, standard inhibitors have had only marginal activity in patients with advanced disease. We here show that, in experimental isogenic models and PDX models with PI3K and PTEN alterations, PI3K inhibitors and rapalogs are weak inhibitors of TORC1 targets and slow but do not suppress the in vivo growth of these tumors. Revolution Medicines has developed a series of bi-steric selective and potent mTORC1 inhibitors that inhibit the phosphorylation of 4EBP-1, S6K and other mTORC1 substrates at concentrations that do not affect TORC2 substrates and thus do not induce the hyperglycemia caused by downregulation of AKT signaling by pan-mTOR kinase inhibitors. We have explored the biologic and anti-tumor effects of these inhibitors in models of endometrial cancer with coexistent PI3K mutation and PTEN inactivation. The mTORC1 kinase selective bi-steric inhibitor RMC-6272 can potently suppress both mTORC1 activity and the growth of these tumor cells in vitro. Moreover, in contrast to PI3K inhibition, RMC-6272 effectively inhibited the phosphorylation of mTORC1 kinase substrates and completely suppressed the growth in vivo of multiple PDXs with this genotype without inducing hyperglycemia or causing weight loss in the mice. The results suggest that dysregulation of TORC1 activity is an important driver of endometrial carcinomas with coexistent PTEN inactivation and PI3K mutations and that selective TORC1 kinase inhibitors may prove to be useful therapeutics in this context. The bi-steric mTORC1 kinase inhibitor RMC-5552 is the first clinical candidate of this class and clinical testing is ongoing (NCT04774952). Citation Format: Hilla Solomon, Radha Mukherjee, Xiaoping Chen, HuiYong Zhao, Elisa de Stanchina, Britta Weigelt, Alison M. Schram, Carol Aghajanian, Mallika Singh, Jan Smith, Neal Rosen. Effective in vivo treatment of endometrial tumor models with coexistent mutant PI3K and PTEN inactivation with a selective bi-steric mTORC1 kinase inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB089.
Abstract 4069: The potent quadruplex-binding compound SOP1812 shows anti-tumor activity in patient-derived <i>in vivo</i> models of pancreatic cancer
Authors: Stephen Neidle, Ahmed Ahmed, Richard Angell, Sally Oxenford
Journal: Cancer Research (2022)

Abstract The compound SOP1812, a tetra-substituted naphthalene diimide derivative has been previously disclosed to have single-digit nM anti-proliferative activity in a panel of human pancreatic ductal adenocarcinoma (PDAC) cell lines (Ahmed et al., ACS Med Chem Lett, 2020, 11, 1634-1644). It also has significant anti-tumor activity in the MIA-PACA2 xenograft model for PDAC as well as in the more demanding KPC model. We now report that this compound also shows significant anti-tumor activity in three patient-derived xenograft (PDX) models for PDAC. One is from a primary PDAC tumor at stage I and the two others from patients with stage IV PDAC (PDX tumor studies undertaken under contract by Champions Oncology). Transcriptome studies on cellular responses to SOP1812 have previously demonstrated that expression of a number of oncogenes and related signaling pathways are down-regulated by this agent. The promoter regions of these genes have an over-representation of quadruplex-containing sequences and several have also been shown by us to be also down-regulated in treated tumor xenografts. Our working hypothesis that the mechanism of action of SOP1812 in vivo involves targeting of quadruplex-containing genes, is also supported by the PDX data since these tumors have elevated levels of several quadruplex-containing genes previously identified by us in cells and in vivo. SOP1812 is bio-available at therapeutic doses and is well tolerated at these levels in these animal models. It is currently being evaluated as a candidate for clinical development by Qualigen Therapeutics Inc. Citation Format: Stephen Neidle, Ahmed Ahmed, Richard Angell, Sally Oxenford. The potent quadruplex-binding compound SOP1812 shows anti-tumor activity in patient-derived in vivo models of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4069.
Abstract 1004: Growth hormone upregulates tumor-derived exosomal distribution of EMT mediators and multi-drug efflux pumps in melanoma
Authors: Prateek Kulkarni, Reetobrata Basu, John J. Kopchick
Journal: Cancer Research (2022)

Abstract Melanoma is the most aggressive form of skin cancer with a dismal 5-year survival rate of 16% at the metastatic stage of the disease. Exosomes have recently emerged as a critical mediator of cancer therapy resistance by regulating epithelial to mesenchymal transition (EMT) and drug efflux. Exosomes are extracellular vesicles (diameters 30-150nm) released from almost all types of cells including tumor cells which package and transfer proteins, RNA, and lipids (often called cargo) from one cell to another. This intercellular communication via exosomes has been reported to induce a drug-resistant phenotype across the tumor by transporting ABC multidrug transporters and mediators of EMT. Multiple studies have established that pituitary-, or tumor- or tumor microenvironment-derived growth hormone (GH) promotes EMT and drug resistance in cancer by binding to GHR-expressing tumor cells. A question arises: Does GH exert this effect across the tumor population via modulating tumor-derived exosomal cargo? No study has yet directly assessed the effect of GH on exosomes in terms of modulating EMT or drug resistance. We isolated exosomes from human melanoma cells with differential levels of GHR expression, following treatment with combinations of GH, anti-cancer drugs, and the GHR antagonist, pegvisomant. We observed no change in the quantity of tumor-derived exosomes with changes in GH action. However, we found significant upregulation of multidrug efflux pumps ABCB1, ABCC1, ABCC2, and ABCG2 in GH-treated tumor exosomes. Importantly, treatment of naïve melanoma cells with these exosomes increased their drug efflux rate and reduced drug retention. Exosomes derived from pegvisomant treated melanoma cells showed markedly reduced ABC transporter contents and did not increase the efflux rate of naïve tumor cells. A similar trend in matrix metalloproteinases (MMP2, MMP9) and TGFb levels in isolated exosomes as well as TGFb signaling and invasion capacity in naïve tumor cells treated with isolated exosomes were observed. These results present a unique effect of GH on tumor-derived exosomal content modulation towards propagating a drug-resistant tumor phenotype in naïve cancer cells. Acknowledgment: This work was supported in part by the State of Ohio’s Eminent Scholar Program that includes a gift from Milton and Lawrence Goll, by the AMVETS, and Ohio University’s Student Enhancement Award and Edison Biotechnology Institute. Citation Format: Prateek Kulkarni, Reetobrata Basu, John J. Kopchick. Growth hormone upregulates tumor-derived exosomal distribution of EMT mediators and multi-drug efflux pumps in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1004.
Abstract 3345: ERAS-601, a potent inhibitor of SHP2, synergistically enhances the activity of a FLT3 inhibitor, gilteritinib, in FLT3-mutated AML tumor models
Authors: Leenus Martin, Roopal Patel, Jingchuan Zhang, Robin Nevarez, Taylor Congdon, Les Brail, Robert Shoemaker
Journal: Cancer Research (2022)

Abstract ERAS-601 is a potent, small molecule allosteric inhibitor of wildtype SHP2, a non-receptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene. ERAS-601 inhibits wildtype SHP2 biochemically with an IC50 of 4.6 nM and demonstrates selectivity across panels of 300 kinases and 12 phosphatases. SHP2 mediates upstream receptor tyrosine kinase (RTK) signaling via its phosphatase-mediated regulation of guanine nucleotide exchange factors (GEFs). ERAS-601 inhibits the SHP2 dependent cycling of KRAS from the inactive GDP-bound state to the active GTP-bound state and demonstrates anti-proliferative activity in FLT3-mutated human cancer cells. Gilteritinib is a second-generation FLT3 inhibitor and has demonstrated clinical activity, but emerging resistance limits the benefit of monotherapy. Here, we explored the combination of gilteritinib with ERAS-601 in FLT3 mutated AML nonclinical models. The combination of ERAS-601 with gilteritinib inhibits the oncogenic RAS/MAPK signaling as measured by pERK1/2 and synergistically inhibits the cellular viability of FLT3-mutated AML cells in vitro. The combination of ERAS-601 with gilteritinib achieves a more durable tumor growth inhibition than the respective gilteritinib and ERAS-601 monotherapies in vivo. These preclinical data support the clinical development of ERAS-601 in combination with gilteritinib in FLT3-altered AML. Citation Format: Leenus Martin, Roopal Patel, Jingchuan Zhang, Robin Nevarez, Taylor Congdon, Les Brail, Robert Shoemaker. ERAS-601, a potent inhibitor of SHP2, synergistically enhances the activity of a FLT3 inhibitor, gilteritinib, in FLT3-mutated AML tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3345.
Abstract 2348: Contribution of the GR/LEDGFp75 axis to prostate cancer chemoresistance
Authors: Evelyn S. Sanchez Hernandez, Greisha L. Ortiz Hernandez, Pedro T. Ochoa, Christian R. Gomez, Carlos A. Casiano
Journal: Cancer Research (2022)

Abstract Prostate cancer (PCa) is the second leading cause of cancer deaths in the U.S., disproportionally affecting African American (AA) men. Glucocorticoids (GCs) are administered to PCa patients and have been implicated in therapy resistance. This may be critical to AA men with PCa since they have elevated endogenous GCs levels compared to Caucasian American (CA) men. GCs bind to the glucocorticoid receptor (GR) to exert their actions. The mechanisms of GR-mediated chemoresistance, and its possible contribution to PCa mortality disparities are unknown. We demonstrated that GCs upregulate the chemoresistance-associated protein and transcription co-activator LEDGF/p75 in PCa cells and identified consensus GR binding sites in the promoter region of this protein. Given that both GR and LEDGF/p75 are components of the RNA polymerase II transcription complex, we hypothesized that GR transcriptionally upregulates LEDGF/p75 and then interacts with it to enhance taxane resistance in PCa cells. Pharmacological and genetic inhibition of GR in a panel of docetaxel (DTX)-sensitive and -resistant PCa cells decreased the expression of LEDGF/p75, confirming its status as a candidate GR target gene. However, silencing of LEDGF/p75 had no effects on GR expression. Immunoprecipitation studies revealed that GR and LEDGF/p75 interact in DTX-resistant PCa cells. This interaction was confirmed by confocal microscopy. Immunohistochemical analysis of GR and LEDGF/p75 expression in normal and tumor prostate tissues was performed, and the results are currently being analyzed. Our studies use a mechanistic approach to evaluate the potential contribution of the GR-LEDGF/p75 axis to PCa chemoresistance. Evaluating the co-expression of these proteins in racially diverse PCa tissues may also reveal race-related differential expression, providing insights into the potential contribution of this axis to PCa chemoresistance and mortality disparities. Citation Format: Evelyn S. Sanchez Hernandez, Greisha L. Ortiz Hernandez, Pedro T. Ochoa, Christian R. Gomez, Carlos A. Casiano. Contribution of the GR/LEDGFp75 axis to prostate cancer chemoresistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2348.
Abstract 267: Xenograft models of non-metastatic non-small cell lung cancer reveals micrometastasis-associated single cell composition
Authors: Kanve Nagaraj Suvilesh, Yulia I. Nussbaum, Vijay Radhakrishnan, Yariswamy Manjunath, Diego M. Avella, Kevin F. Staveley-O’Carroll, Eric T. Kimchi, Aadel A. Chaudhuri, Chi-Ren Shyu, Guangfu Li, Klaus Pantel, Wesley C. Warren, Jonathan B. Mitchem, Jussuf T. Kaifi
Journal: Cancer Research (2022)

Abstract Background: Circulating tumor cells (CTCs) represent micrometastatic disease and may offer unique insights into future recurrences in lethal malignancies, including non-small cell lung cancer (NSCLC). Due to CTC rarity and limited stability, no CTC-derived xenograft (CDX) models have ever been generated from non-metastatic NSCLC patients directly. Alternative strategies are needed to molecularly characterize CTCs in this potentially curable patient group. Methods: Surgically resected NSCLC primary tumor tissues were implanted in immunodeficient mice to establish ten patient-derived xenografts (PDXs). CTCs from 2/10 PDX models led to generation of two stable metastatic models that were studied by single cell sequencing. Results: Single cell analysis revealed an additional alveolar epithelial type II (AT2) population in metastatic tumors, besides a common AT2 cluster in PDX/metastatic tumors. This was consistent with an external validation set analysis in primary and metastatic NSCLC patient tumors. Further, AT2 clusters of metastatic tumors expressed higher cancer stemness genes versus primary PDX tumor that was recapitulated in patients primary and metastatic tumors. Conclusions: Stable metastatic models from early stage NSCLC patients can be generated with CTCs from PDX models. The distinct AT2 population identified in CDX tumors with cancer stemness features might be critical mediator of metastasis that deserves further study to discover personalized strategies against NSCLC micrometastases. Citation Format: Kanve Nagaraj Suvilesh, Yulia I. Nussbaum, Vijay Radhakrishnan, Yariswamy Manjunath, Diego M. Avella, Kevin F. Staveley-O’Carroll, Eric T. Kimchi, Aadel A. Chaudhuri, Chi-Ren Shyu, Guangfu Li, Klaus Pantel, Wesley C. Warren, Jonathan B. Mitchem, Jussuf T. Kaifi. Xenograft models of non-metastatic non-small cell lung cancer reveals micrometastasis-associated single cell composition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 267.
Facilitators and barriers to the implementation of improved solid fuel cookstoves and clean fuels in low-income and middle-income countries: an umbrella review
Authors: Esther A Boudewijns, Maria Trucchi, Rianne M J J van der Kleij, Debbie Vermond, Charlotte M Hoffman, Niels H Chavannes, Onno C P van Schayck, Bruce Kirenga, Evelyn A Brakema
Journal: The Lancet Planetary Health (2022)
Abstract 2710: Associations between structural variant signatures and drug sensitivity in cell lines
Authors: Simona Dalin, Frank Dubois, Shu Zhang, Alexander Crane, Jeremie Kalfon, Javad Noorbakhsh, Rameen Beroukhim
Journal: Cancer Research (2022)

Abstract Structural variants (SVs) within the cancer genome reflect defects in DNA damage repair, impact gene regulation, and alter the genomic landscape. SVs impact a larger fraction of the cancer genome than any other genetic aberration, yet their effects on modulating therapeutic response have been largely uncharacterized. Patterns of rearrangements, otherwise known as signatures, vary across tumor and tissue type, and can indicate underlying biological mechanisms responsible for cancer etiology. We have extracted SV signatures from whole genome sequencing data from hundreds of cancer cell lines. Using datasets indicating the cell lines’ response to over a thousand small molecule inhibitors, we have identified associations between SV signatures and response to therapeutics. These results will enhance our understanding of mechanisms underlying rearrangement signatures and nominate new biomarkers of drug response. Citation Format: Simona Dalin, Frank Dubois, Shu Zhang, Alexander Crane, Jeremie Kalfon, Javad Noorbakhsh, Rameen Beroukhim. Associations between structural variant signatures and drug sensitivity in cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2710.
Abstract LB066: Targeting low density lipoprotein receptors in the pancreatic adenocarcinoma
Authors: Leo Flores, Xuewei Qu, Cedric Malicet, Pascaline Lecorche, Ebrahim Delpassand, Jamal Temsamani, Izabela Tworowska
Journal: Cancer Research (2022)

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor 5-year overall survival rate at all stages of disease (7-10%). The immunohistochemistry of pancreatic cancer tissue has shown a significantly higher level of positive LDLR (low-density lipoprotein receptor) staining in primary tumors compared to the normal adjacent pancreas. LDLR is overexpressed in the epithelial pancreatic adenocarcinoma, irrespectively of tumor size, stage, and aggressiveness. The objective of this study was to determine the LDLR-targeting properties of 68Ga-labeled peptide conjugate, 68Ga-RMX-VH, in pancreatic adenocarcinoma cell lines. Methods: RMX-VH peptide conjugate (25-50μg) was labeled with 68Ga (50-100mCi, ITM Germany) in mild conditions in the presence of scavenger, sodium ascorbate (8mg/ml). The cellular uptake and competition studies of the radiotracer (15μCi/well) were completed in multiple pancreatic adenocarcinoma cell lines and in vivo in PDAC xenografts generated in athymic nude mice. The PET/CT images were acquired using a G4 PET/X-ray camera (Sofie Biosciences; 10min/scan) at 1h, 2h post-injection. This study determined in vivo and in vitro time-dependent accumulation of this agent in LDLR-overexpressing pancreatic adenocarcinoma cells. Results: 68Ga-RMX-VH was synthesized with higher than 95% radiochemical purity. The radiotracer was incubated in pancreatic adenocarcinoma cell lines for 1h and has shown the highest uptake in HPAF-II (6.7%ID/mg) and BxPC-3 (5.3 %ID/mg) and MiaPaCa2 (4.75 %ID/mg), respectively. Western blot showed a variable level of LDLR overexpression in human pancreatic cancer cells. The microPET imaging studies confirmed rapid accumulation and retention of radiotracer in the tumor (1.18 %ID/g) and elimination through kidneys (4.5 %ID/g) and bladder (SUV ratio of tumor to kidneys: 0.21). These results correlate with previously reported retention of the agent in Pk4a pancreatic adenocarcinoma. Conclusions: RMX-VH has the potential to evaluate the role of LDL receptors in pancreatic adenocarcinoma. We have initiated the exploratory clinical study of this agent in LDLR-overexpressing solid tumors, including pancreatic adenocarcinoma. Citation Format: Leo Flores, Xuewei Qu, Cedric Malicet, Pascaline Lecorche, Ebrahim Delpassand, Jamal Temsamani, Izabela Tworowska. Targeting low density lipoprotein receptors in the pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB066.
High-Intensity Interval Training vs Moderate-Intensity Continuous Training for Women Undergoing Cardiovascular Rehabilitation
Authors: Erik H. Van Iterson, Luke J. Laffin, Leslie Cho
Journal: JAMA Cardiology (2022)

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